MEDICAL PHARMACOLOGY PCOL 425

FALL 2009 CHOLINERGIC AGONISM AND ANTAGONISM MODULE

MARCELO G. BONINI
Assistant Professor
College of Medicine
mbonini@uic.edu
312-996-4741

Overview
- Cholinergic action
The junction, molecular mechanism, sites of action
- Muscarinic Receptor
Structure, types, coupling with G-Proteins
- Cholinomimetic Drugs
Structure, general features, organ effects
- Cholinomimetic Drugs
Therapeutic uses, toxicology
- Muscarinic Antagonism
Drugs, therapeutic uses, toxicity

Neurons and neurotransmitters general overview

MOVIE

http://www.youtube.com/watch?v=DF04XPBj5uc

Generalized Cholinergic Junction

Acetylcholine binding and receptor structural

changes

Cholinergic action (molecular mechanism)

Intracellular signaling triggered by acetylcholine in the smooth muscle

Main molecular players: M3, Heterotrimeric protein Gq, PLC/IP3, Ca(2+), MLCK

Cholinergic action (molecular mechanism)

Intracellular signaling triggered by acetylcholine in the Heart

Main molecular players: M2, heterotrimeric G Protein Gi, Adenylyl cyclase

Cholinergic action (molecular mechanism)

Intracellular signaling triggered by acetylcholine in the endothelium

eNOS
Nitric oxide synthase

eNOS

L-Arg
L-Citruline

NO

Major molecular players: M3, heterotrimeric G Protein Gq, Ca(2+)-CaM, eNOS, NO

Cholinergic action (molecular mechanism)

acetylcholine mediated endothelium-dependent vasodilation

Start Here
+ACh
NO probe

- ACh
NO probe

Cholinergic action (molecular mechanism)

(endothelium present)

(endothelium absent)

Endothelium dependence of Ach-induced vasodilation of

pre-constricted arterial rings

Sites of Cholinergic Activity

-Preganglionic synapses of both sympathetic and parasympathetic ganglia
- Parasympathetic postganglionic neuroeffector junctions
- All somatic motor end plates on skeletal muscles
RECEPTOR

INTRACELLULAR
TRANSDUCER

ELECTRICAL
MECHANICAL
PHYSIOLOGICAL
RESPONSES

M2

Gi

M4

Go

Adenylyl cyclase
cAMP

Hyperpolarization (heart)
Cardiac inhibition
Antagonism of smooth
muscle relaxation

M1

M3

M5

Gq
Phospholipase C
Diacyl-glycerol IP3

Depolarization
Smooth muscle contraction
Glandular secretion

Muscarinic receptor types

experiments that led to their discovery

M1 - Neurotransmission in Cortex and Ganglia

(-/-) mice - abrogation of pilocarpine induced seizures
M2 - Agonist-mediated bradycardia, tremor, autoinhibition of release in several
brain regions
(-/-) mice - loss of oxytremorine-induced tremors; loss of
agonist-induced bradycardia; diminished hypothermia
M3 - Smooth muscle contraction, gland secreation, pupil dilation, food intake
and possibly weight gain
(-/-) mice - loss of agonist-induced bronchoconstriction,
higher basal pupil dilation, reduction of
agonist-induced salivation
M4 and M5 Central Nervous System (CNS) roles.

Classes of cholinergic stimulants

Direct-acting

Indirect-acting

Receptor agonists

Cholinesterase inhibitors
Carbamates

Choline esters
ACETYLCHOLINE
BETHANECOL

Alkaloids
PILOCARPINE

PHYSOSTIGMINE
NEOSTIGMINE
PYRIDOSTIGMINE
EDROPHONIUM

Phosphates
ISOFLUROPHATE
Antidote
PRALIDOXIMINE

Chemical Structure of Cholinergic agonists

Quaternary ammonium

Tertiary amine

Pilocarpine source/history
Chewing pilocarpus caused salivation

Amazon

Experiments performed in Brazil in 1874, isolated in 1875, methacholine and

carbachol studies in 1911

Absorption, metabolism, distribution

- Absorption: polarity dependent (poor for ACh,
quaternary ammonium), intravenous,
subcutaneous and intramuscular for local effects
(Ach)
- Metabolism: Highly dependent on the
susceptibility to acetylcholinesterase (AChE)
Compound
Acetylcholine chloride
Methacholine chloride
Carbachol chloride
Bethanechol chloride

Susceptibility (AChE)
High (++++)
Low (+)
Negligible
Negligible

Muscarinic
Effect
High (limited by AChE)
Highest (++++)
Medium (++)
Medium (++)

Organ effects Eye/Cardiovascular

- Eyes: contraction of ciliary muscle and smooth muscle of
the iris sphincter (miosis) aqueous humor outflow,
drainage of the anterior chamber
- Cardiovascular: Bradycardia (possibly preceded by
tachycardia), vasodilation (all vascular beds including
pulmonary and coronary M3) and hypotension,
reduction of the contraction strength (atrial and
ventricular cells, IK+ , ICa2+ diastolic depolarization , NOinhibitable ATP?), negative chronotropic effect (inhibition
of adrenergic activation).

Organ effects GI/urinary bladder

- GI - increases in tone, amplitude of contractions, and peristaltic
activity of the stomach and intestines, enhances secretory
activity of the gastrointestinal tract.

- Urinary bladder - increase ureteral peristalsis, contract the

detrusor muscle of the urinary bladder, increase the maximal
voluntary voiding pressure, and decrease the capacity of the
bladder.

- Other effects Increased secretion from all glands that

receive parasymphatetic enervation (salivary, lacrimal,
tracheobronchial, digestive and exocrine sweat glands)
- IMPORTANT - BROCHOCONSTRICTION

Therapeutic uses (BETHANECHOL)

Bethanechol chloride (carbamylmethylcholine chloride; URECHOLINE)

Stimulant of the smooth muscle of the GI tract and the urinary bladder.

Postoperative abdominal distension and gastric retention or gastroparesis.

Urinary retention and inadequate emptying of the bladder when organic
obstruction is absent:
- postoperative
- postpartum urinary retention
- certain cases of chronic hypotonic or neurogenic bladder.
-alternative to pilocarpine to promote salivation Xerostomia (dryness of the
mouth).
-Sjogren syndrome (immunologic disorder with destruction of the
exocrine glands) leading to mucosal dryness

Administration/Precaution/Toxicity

Bethanechol should be administered only by the oral or subcutaneous route for systemic effects;
they also are used locally in the eye.
Antidote - atropine.
Epinephrine may be used to overcome severe cardiovascular or bronchoconstrictor responses.
Among the major contra-indications to the use of the choline esters are asthma,
hyperthyroidism, coronary insufficiency, and acid-peptic disease.

Bronchoconstrictor action could precipitate an asthmatic attack

Hyperthyroid patients may develop atrial fibrillation.

Hypotension induced by these agents can severely reduce coronary blood flow, especially if it is
already compromised.

The gastric acid secretion produced by the choline esters can aggravate the symptoms of acidpeptic disease.

POSSIBLE SIDE EFFECTS : sweating (very common), abdominal cramps, a sensation of tightness in
the urinary bladder, difficulty in visual accommodation for far vision, headache, and salivation.

Therapeutic use/toxicity
(carbachol/methacholine)

Carbachol usually is not employed for these purposes

because of its relatively larger component of nicotinic
action at autonomic ganglia.
The unpredictability of the intensity of response has
virtually eliminated the use of methacholine or other
cholinergic agonists as vasodilators and cardiac
vagomimetic agents.

Methacholine chloride (acetyl-b-methylcholine chloride;

PROVOCHOLINE) may be administered for diagnosis
of bronchial hyperreactivity and asthmatic conditions.

Toxicity/Mycetism
Exageration of all symptoms of muscarinic agonism
Significance: Higher consumption of wild mushrooms
(culinary)

A. muscaria
30-60 minutes, salivation, lacrimation, excessive sweating, nausea, vomiting
diarrhea, bronchospasm, headache, visual disturbances, abdominal colic,
bradychardia, hypotension, shock
ALL SYMPTOMS REVERTED BY ATROPINE1 - 2 mg intramuscular

Mycetism/non muscarinic

Amanita phalloides deadly nightcap

Inhibits mRNA synthesis 24 h symptom free period followed by liver and
kidney malfunction, death within 4-7 days

A. phalloides

A. muscaria

Muscarinic antagonism

Attropa belladona

History/sources

Atropa belladona - used in the renaissance

Deadly nightshade - used in the middle ages to produce polonged
poisoning

Jimson plant leaves burned in India to treat Asthma (1800) purification

of atropine (1831)

Muscarinic Antagonists

ATROPINE

SCOPOLAMINE

Muscarinic Antagonists
ATROPINE

SCOPOLAMINE

Attropa belladona

- Atropine and Scopolamine are belladona alkaloids

(competitive inhibitors)
-Drugs differ in their CNS effects, scopolamine permeates the
blood-brain barrier
-At therapeutic doses atropine has negligible effect upon the CNS,
scopolamine even at low doses has prominent CNS effects.

Mechanism of drug action

- Competitively block muscarinic receptors
- Salivary, bronchial, and sweat glands are
most sensitive to atropine
- Smooth muscle and heart are intermediate
in responsiveness
- In the eye, causes pupil dilation and difficulty for far
vision accomodation
- Relaxation of the GI, slows peristalsis

Effect of muscarinic inhibitor in the eye

Pupil dilation vs accomodation

Effect of muscarinic inhibition in the

heart and salivary glands

- Increases the heart rate after a transient bradychardia at the low dose
- Diminishes gland excretory function

Graphic summary of atropine effects

Organ effect drug review

Antidotes
ORGAN

DRUG

APPLICATION

Benztropine
Scopolamine

Treat Parkinsons disease

Prevent/Reduce motion sickness

Eye

Atropine

Pupil dilation

Bronchi

Ipatropium

Bronchodilate in Asthma, COPD

GI

Methscopolamine

Reduce motility/cramps

GU

Oxybutinin

Treat transient cystitis

Postoperative bladder spasms

CNS

Toxicity of muscarinic antagonists

DRY AS BONE, RED AS A BEET, MAD AS HATTER.
Dry is a consequence of decreased sweating, salivation
and lacrimation
Red is a result of reflex peripheral (cutaneous)
vasodilation to dissipate heat (hyperthermia)
Mad is a result of the CNS effects of muscarinic inhibition
which can lead to sedation, amnesia (hypersensitivity),
or hallucination

Preview
- Indirect cholinergic agonism (Inhibition of AChE)
- Nicotine-acetylcholine agonism / antagonism
- Therapeutic use and toxicology